Effect of celecoxib on cyclooxygenase-1-mediated prostacyclin synthesis and endothelium-dependent contraction in mouse arteries.

MedLine Citation:

PMID:
23127498
Owner:
NLM
Status:
Publisher

Abstract/OtherAbstract:

This study aimed to determine whether a cyclooxygenase-2 (COX-2) inhibitor celecoxib influences endothelium-dependent contraction independent of its action on COX-2 and, if so, the underlying mechanism(s). Abdominal aortas and/or carotid arteries from C57BL/6 mice or those with genetic COX-2 deficiency (COX-2(-/-)) were isolated for functional and/or biochemical analyses. Result showed that following NO synthase inhibition celecoxib not only reduced the contraction evoked by acetylcholine in C57BL/6 abdominal aorta, but also that in COX-2(-/-) mice showing a comparable magnitude. Notably, the IC(50) of celecoxib obtained in COX-2(-/-) abdominal aorta was only ~0.364μM. Also, celecoxib exhibited a similar effect on COX-2(-/-) carotid arteries. Interestingly, celecoxib was not only found to inhibit the production of the prostacyclin (PGI(2)) metabolite 6-keto-PGF(1α) in COX-2(-/-) aortas, but also caused a reduction in the contraction evoked by PGI(2), by the α(1)-adrenergic agonist phenylephrine, or by 30mM K(+)-induced depolarization in COX-2(-/-) and/or C57BL/6 abdominal aorta. Moreover, N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS398), another COX-2 inhibitor, also reduced the contraction evoked by acetylcholine or by 30mM K(+)-induced depolarization in COX-2(-/-) mice. These results demonstrate explicitly that in mouse arteries celecoxib not only inhibits COX-1-mediated synthesis of PGI(2) and probably some other prostanoids, but also causes a reduction in vessel contractility that is independent of either COX-2 or COX-1, leading to an inhibition of COX-1-mediated endothelium-dependent contraction with an IC(50) value far below that of it considered for COX-1. Also, our data suggest that such effects of celecoxib could be possibly shared by some other COX-2 inhibitors, such as NS398.